Voltage-gated ion channels play a critical role in the electrical activity of neuronal and muscle cells. Large families of voltage-gated ion channels (e.g., sodium channels) have been identified. These ion channels have been the target of significant pharmacologic study, due to their potential role in a variety of pathological conditions.
Pain
Biophysical and pharmacological studies have identified the sodium channel isoforms NaV1.3, NaV1.7, NaV1.8, and NaV1.9 as particularly important in the pathophysiology of pain, in particular neuropathic pain. Recently, gain-of-function mutations in SCN9A, the gene which encodes NaV1.7, have been linked to two human-inherited pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder, while loss-of-function mutations in SCN9A have been linked to complete insensitivity to pain. Dib-Hajj et al, Pain Medicine 10(7):1260-1269 (2009) (abstract). Pain conditions affect approximately 100 million U.S. adults at a cost of $560-635 billion annually in direct medical treatment costs and lost productivity. Relieving Pain in America, National Academies Press, Washington, D.C. (2011), page 2. Unfortunately, current treatment options typically provide only partial pain relief, and are limited by inconvenient dosing and by side effects, such as somnolence, ataxia, edema, gastrointestinal discomfort and respiratory depression. Therefore, novel compounds are desirable to address the shortcomings of presently available treatment options.
Prediabetes and Diabetes
Prediabetes and diabetes describe a group of metabolic diseases with high blood sugar levels over longer periods of time. Diabetes can result from insufficient production of the peptide hormone insulin. In other cases, diabetes can result from insulin resistance, i.e., an inability of cells to respond properly to insulin. If the blood sugar levels are higher than normal, but not high enough for a diagnosis of diabetes, the subject is prediabetic. There are three main types of diabetes: First, Type 1 results from the body's failure to produce sufficient levels of insulin. Second, Type 2 results from insulin resistance. Third, Gestational diabetes occurs when pregnant women without a previous history of diabetes develop a high blood glucose level. Another type of diabetes is latent autoimmune diabetes in adults (LADA). LADA is the most common term describing patients with a type 2 diabetic phenotype combined with islet antibodies and slowly progressive cell failure.
Type 2 diabetes, for example, is a serious and prevalent disease. Approximately 25.8 million people in the United States alone suffer from diabetes, whereby type 2 diabetes accounts for about 90-95% of all diagnosed diabetes cases. U.S. Patent Application Publication No. 2014/0228353 A1 at paragraph [0002]. The number of Americans with diabetes has more than tripled from 1980 to 2008. Id. Diabetes is also increasingly prevalent in other parts of the world, such as in certain Asian countries. Id. Rapid lifestyle and economic changes in, e.g., India and China, have led to a more sedentary lifestyle and poorer diet among the overall population, causing diabetes to become a major health concern. Id. There remains a continued need for novel and improved therapies that address this growing health concern.